Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse spontaneous liver tumors of Trim24/TIF1a-null animals

ABSTRACT: The transcriptional coregulator Trim24 (formerly known as TIF1a) functions in mice as a liver-specific tumor suppressor. Mice carrying a null mutation in the Trim24 gene all develop hepatocellular carcinoma (HCC). We used microarrays to identify the alterations in gene expression patterns associated with loss of Trim24 and consequent HCC development. Experiment Overall Design: Five independent liver tumor (HCC) samples taken from five Trim24 knockout (KO) mice and five normal liver tissue samples taken from wild-type (WT) littermate controls were used for RNA extraction and hybridization on Affymetrix microarrays.

ORGANISM(S): Mus musculus

SUBMITTER: RÃ©gine Losson

PROVIDER: E-GEOD-9012 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha.

Khetchoumian Konstantin K Teletin Marius M Tisserand Johan J Mark Manuel M Herquel Benjamin B Ignat Mihaela M Zucman-Rossi Jessica J Cammas Florence F Lerouge Thierry T Thibault Christelle C Metzger Daniel D Chambon Pierre P Losson Régine R

Nature genetics 20071118 12

Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmac ...[more]

PMID: 18026104

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Project description:Recent genetic studies in mice have established a key role for the nuclear receptor coregulator Trim24 in liver tumor suppression and provided evidence that Trim24 suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor alpha (Rara)-dependent transcription and cell proliferation. However, it is unknown which downstream targets of Rara regulated by Trim24 are critical for tumorigenesis. We report here that loss of Trim24 results in the overexpression of interferon (IFN)/STAT pathway genes in the liver, a process that occurs early in tumorigenesis and is more pronounced in tumors, despite the enhanced expression, late in the disease, of negative regulators such as Usp18, Socs1 and Socs2. Remarkably, Rara haplodeficiency, which was previously shown to suppress tumor development in Trim24-/- mice, also suppresses overexpression of the IFN/STAT pathway, thus providing evidence for a cross-pathway control that may be relevant to the transformation process. Biochemical studies revealed that Trim24 binds to the retinoic acid (RA)-responsive element in the Stat1 promoter in a RA-dependent manner and represses RA-induced transcription from this promoter. Together, these results identify Trim24 as a novel regulator of the IFN/STAT pathway and indicate that Trim24-mediated repression of the IFN/STAT signaling through Rara inhibition may play a critical role in preventing liver cancer. Generation of Trim24-/- mice has been described previously (Khetchoumian et al., 2007) by gene disruption. To generate compound mutant mice with a single allele of Rara deleted in the Trim24 -/- mutant background, we crossed Trim24 -/- mice with Rara+/- mice. The resulting Trim24+/- Rara+/- mice were generated in the hybrid (C57BL/6 (60%), 129/Sv (40%)) genetic background. These double heterozygous Trim24+/- Rara+/- mice were intercrossed to generate Trim24 -/-, Trim24 -/- Rara+/- and wild-type mice. Transcriptional profiling of mice at 5-weeks and 14-weeks of age.

Dataset Information

Transcription profiling of mouse spontaneous liver tumors of Trim24/TIF1a-null animals

Publications

Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha.

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